Sarcoidosis and Alpha-1 Antitrypsin Deficiency are uncommon, understudied diseases that lack safe, effective treatments. Sarcoidosis is a multisystem granulomatous disorder that involves the lungs in over 90% of affected individuals and may cause end-stage pulmonary fibrosis and death. With an incidence of ~10-40 per 100,000 people in the U.S., sarcoidosis represents a significant health problem and health disparity concern. The pathologic hallmarks of sarcoidosis are non-caseating granulomas and polarized Th1 immunity at sites of disease. There is tremendous clinical heterogeneity with respect to organ involvement, severity and clinical course with both remitting and chronic progressive disease. There are no diagnostic tests for sarcoidosis except for biopsy of affected tissues, and no clinically useful biomarkers for risk stratification, prognosis or response to treatment. The goals of the study are to identify molecular abnormalities and their relationship to disease characteristics by employing genomics and microbiomics analyses of systematically phenotyped subjects, and to elucidate pathogenic mechanisms and identify predictors of disease. Proposed Aim 1 studies will systematically phenotype newly diagnosed sarcoidosis patients and provide lung, blood and tissue samples for study wide genomic and microbiomic analyses. Study-wide protocols will be established to evaluate the antigen specific immune responses to candidate pathogenic microbial antigens in sarcoidosis and correlate these dynamic measures with clinical phenotype and genomic/microbiomic analyses. Proposed Aim 2 studies will explore the hypothesis that serum amyloid A, an acute phase reactant and amyloid precursor protein, is a central mediator of chronic inflammation and fibrosis by correlating SAA levels in blood, lung and tissues with clinical phenotype and genomic/microbiomic analyses, assessing the proinflammatory and profibrotic cytokine-inducing effects of SAA on blood and lung cells in sarcoidosis, and identifying the receptor pathways that mediate these effects. These studies may establish links between specific clinical phenotypes, microbial etiologies, and common pathogenic mechanisms to provide a framework for new therapeutic approaches to sarcoidosis.